PROJECT SUMMARY: Neurovascular coupling, the close spatial and temporal relationship between neural activity and hemodynamics that regulates delivery of metabolic substrates to meet the demands of neuronal activation, is crucial to the structural and functional integrity of the brain. It also forms the basis of modern neuroimaging techniques such as fMRI that use hemodynamic responses to map brain function. Despite of its significant fundamental and clinical importance, the quantitative relationship between changes in hemodynamics and neural activity including the spatial extent of the coupling remains rudimentary; the quantitative effects of cerebrovascular diseases on neurovascular coupling and their dependence on the severity and progression of the diseases are understudied. Such knowledge gaps impose limitations on the precise clinical interpretation of widely applied neuroimaging techniques, and the therapeutic opportunities to clearly target the impairment of neurovascular coupling for treatment. The objective of this project is to provide spatiotemporally resolved quantification of neurovascular coupling in health and during the progression of stroke and hypertension. The hypothesis is that neurovascular coupling can be quantified and tracked by applying a novel chronic multimodal neural platform that simultaneously map both neural activity and hemodynamic parameters with high spatial- and temporal resolution over weeks to months in behaving animals. This is enabled by our recent development of a novel type of ultraflexible nanoelectronic neural electrodes that provide spatially resolved neural activity recording with seamless tissue integration and chronic optical access. We will combine these electrodes with a novel functional optical imaging system that simultaneously images and quantifies the full-field cerebral blood flow and oxygen tension (pO2). We will apply this multimodal system in behaving mice to quantify neurovascular coupling including the spatiotemporal pattern, the functional form, and the alteration due to progressing ischemia, hypertension and both. The application is highly innovative, in the applicant?s opinion, because it integrates technical advancements at multiple fronts to provide a highly novel and powerful combination of techniques that permits quantification of neurovascular coupling in previously unattainable temporal and spatial regimes. The application is significant, because it is expected to have broad translational importance both in the precise clinical interpretation of neuroimaging techniques, and in the intervention of cerebrovascular diseases where neurovascular coupling is known to be severely compromised. The long-term goal of this project is to understand the impairment of neurovascular coupling in stroke and hypertension with mechanisms similar to those occurred in human patient in order to unravel the mechanism of hypertension as the leading risk factor for stroke, and to improve prevention and intervention strategies for hypertensive stroke patients.